Choice Of Chemotherapy Research Articles

Abstract GS02-01: Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01

Abstract Background: The global, phase 3 TROPION-Breast01 trial (NCT05104866) assessed the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) compared with investigator’s choice of chemotherapy (ICC) in patients (pts) with inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2‒) breast cancer (BC). Primary results were presented at ESMO 2023 (Bardia A, et al. Abstract LBA11). Here we report expanded data from TROPION-Breast01. Methods: Pts aged ≥18 years who had inoperable or metastatic HR+/HER2‒ BC, had disease progression on endocrine therapy (ET) and for whom ET was unsuitable, and had received 1‒2 prior lines of systemic chemotherapy (CT), were eligible. Pts were randomized 1:1 to Dato-DXd (6 mg/kg Q3W) or ICC (eribulin, vinorelbine, capecitabine, or gemcitabine) until progression or unacceptable toxicity. The dual primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1, and overall survival (OS). Results: In total, 732 pts were randomized: 365 to the Dato-DXd arm and 367 to ICC. At data cut-off (Jul 17, 2023), 93/39 pts in the Dato-DXd/ICC groups were ongoing treatment. Pts receiving Dato-DXd had significantly improved PFS vs ICC (HR 0.63 [95% CI 0.52‒0.76]; p<0.0001). Hazard ratios for PFS favored Dato-DXd over ICC across prespecified pt subgroups, including prior lines of CT in the metastatic setting (1 vs 2), prior use of CDK4/6 inhibitor (≤12 months vs >12 months), prior use of endocrine therapy in the metastatic setting ( <6 months vs ≥6 months) and brain metastases (yes vs no). OS data were not mature at this data cut-off. In the Dato-DXd vs ICC arms, 192 (53%) vs 247 (67%) pts had received a subsequent therapy after study treatment discontinuation, including 15 (4%) vs 52 (14%) who received subsequent ADC therapy, and 165 (45%) vs 186 (51%) who received subsequent CT. Median time to first subsequent therapy was 8.2 months in the Dato-DXd arm vs 5.0 months in the ICC arm (HR 0.53 [95% CI 0.45–0.64). Overall, rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was less than half that with ICC. The secondary patient-reported outcome endpoints showed that time to deterioration in physical functioning, pain, and global health status/quality of life were delayed in the Dato-DXd arm compared with ICC. Conclusions: TROPION-Breast01 met its dual primary endpoint of PFS, demonstrating statistically significant and clinically meaningful improvement in PFS with Dato-DXd compared with ICC across all subgroups. Overall, the safety profile and QoL with Dato-DXd was favorable compared with ICC. These data support Dato-DXd as a potential new therapeutic option for pts with inoperable or metastatic HR+/HER2‒ BC who have received 1‒2 prior lines of CT. Citation Format: Aditya Bardia, Komal Jhaveri, Seock-Ah Im, Michelino De Laurentiis, Binghe Xu, Sonia Pernas, Giuliano Borges, David Cescon, Masaya Hattori, Yen-Shen Lu, Noelia Martínez-Jáñez, Erika Hamilton, Shusen Wang, Junji Tsurutani, Kevin Kalinsky, Lu Xu, Sabrina Khan, Neelima Denduluri, Hope Rugo, Barbara Pistilli. Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-01.

Abstract PS08-08: Updated efficacy and safety of SKB264 (MK-2870) for previously treated metastatic triple negative breast cancer (mTNBC) in Phase 2 study

Abstract Background: Patients (pts) with mTNBC have limited treatment options and poor prognosis. The estimated median overall survival (OS) of pts with mTNBC is 12 to 18 months (mo) after diagnosis. SKB264, an antibody drug conjugate (ADC) composed of an anti-TROP2 antibody coupled to a cytotoxic belotecan-derivative via a novel linker with an average Drug to Antibody Ratio (DAR) of 7.4, has shown promising anti-tumor activity and tolerable safety profile in pts with mTNBC (Yin, Y. et al. SABCS 2022). Here, we report the updated data from a Phase 2 expansion cohort for pts with mTNBC (NCT04152499). Methods: Pts with previously treated mTNBC were enrolled to receive SKB264 at 4 mg/kg Q2W or 5 mg/kg Q2W in a non-randomized manner until disease progression or unacceptable toxicity. Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. The primary objective was to assess objective response rate (ORR). Secondary objectives included DoR, PFS, and OS. The TROP2 expression was scored using the semi-quantitative H-score method, and a preliminary cutoff was set as 200. TROP2 expression and its association with anti-tumor activity were retrospectively analyzed. Results: At data cut-off date (May 05, 2023), 59 pts were enrolled (23 in 4 mg/kg, 36 in 5 mg/kg), and 88% (52 pts) had received ≥3 prior lines of therapy for metastatic disease. The median follow-up was 22.8 months (mo; 95% CI, 21.3-25.2). The ORR was 42.4% (25/59, 22 confirmed and 3 unconfirmed) and disease control rate (DCR) was 76.3% (45/59). The median duration of response (DoR) was 11.5 mo (range, 3.7 to 22.1+). Median PFS (mPFS) was 5.7 mo (95% Cl: 3.8, 9.1). Median OS (mOS) was 16.8 mo (95% Cl: 12.7, NE), while 12-mo and 24-mo OS rates were 65.0% and 39.5%, respectively. In the subset of pts with high TROP2 expression (H-score>200, N=32), ORR was 53.1% (including 3 complete response), mDoR was 11.1 mo (range, 3.7 to 22.1+), mPFS was 5.8 mo (95% Cl: 3.7, 13.3), mOS was not reached (95% Cl: 9.7, NE), while 12-mo and 24-mo OS rates were 65.3% and 57.3%, respectively. Treatment-related adverse events (TRAEs) of ≥ Grade 3 severity were reported in 57.6% (34/59) of pts. The most common ≥ Grade 3 TRAEs (≥ 10%) were neutrophil count decreased (25.4%), white blood cell count decreased (23.7%), anemia (22.0%) and platelet count decreased (16.9%). TRAEs leading to dose reduction and dose delay occurred in 13.6% (8/59) and 47.5% (28/59) of pts, respectively. Three pts discontinued treatment due to TRAEs (platelet count decreased, dry eye, anaphylactic shock). No cases of interstitial lung disease (ILD), neuropathy or grade ≥3 diarrhea were observed. Serious TRAEs were reported in 28.8% (17/59) of pts; no deaths associated with TRAEs were observed. Conclusions: The updated data continues to demonstrate that pts with heavily pretreated mTNBC could achieve durable response and a trend of long-term OS benefit from SKB264 treatment, along with a manageable safety profile. Higher response rate was seen in mTNBC pts with high TROP2 expression. A Phase 3 study of SKB264 vs. investigator’s choice of chemotherapy in 3L+ mTNBC (NCT05347134) and a Phase 2 study evaluating SKB264 as monotherapy or combination with anti-PD-L1 antibody in first-line setting (NCT05445908) are ongoing in China. Citation Format: Yongmei Yin, Xinhong Wu, Quchang Ouyang, Min Yan, Lihua Song, YunPeng Liu, Zhongsheng Tong, Cuizhi Geng, Ying Wang, Guohua Yu, Xiang Wang, Ying Cheng, Weihong Zhao, Xiaoping Jin, Yina Diao, Gesha Liu, Mengyu Yang, Yue Yang, Yalan Yang, Lian Lu, Junyou Ge, Jin Li, Qun Li. Updated efficacy and safety of SKB264 (MK-2870) for previously treated metastatic triple negative breast cancer (mTNBC) in Phase 2 study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-08.

Abstract PO4-18-04: An exploratory study of Trastuzumab Deruxtecan neoadjuvant therapy in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy

Abstract Background The current standard of care for neoadjuvant treatment of HER2-positive early-stage breast cancer consists of dual HER2-blockade with trastuzumab (H) plus pertuzumab (P) and polychemotherapy with a pathological complete response (pCR) rate of 31%~50%. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. T-DXd significantly prolonged progression-free and overall survival vs trastuzumab emtansine in HER2-positive unresectable and/or metastatic breast cancer (mBC) previously treated with H and taxane in DESTINY-Breast03 study. HER2-low breast cancer is currently treated as HER2-negative (HER2-low and HER2-zero) breast cancer, with patients stratified according to hormone-receptor (HR) status. In DESTINY-Breast04 study, T-DXd resulted in significantly longer progression-free and overall survival than the physician’s choice of chemotherapy in HER2-low mBC. Given the efficacy of T-DXd monotherapy in HER2-positive or HER2-low mBC, we conduct an exploratory study to evaluate the efficacy and safety of T-DXd in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy, and to identify sensitive biomarkers for T-DXd neoadjuvant therapy. Methods Eligible patients were women aged 18 years to 75 years with clinical stage cT2–cT4/cN0–cN3/cM0 (stage II–III) invasive breast cancer (>2 cm in size) confirmed as HER2-positive (immunohistochemistry [IHC] 3+) or HER2-low (IHC2+ or IHC1+/situ hybridization-negative). Patients are required to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and baseline left ventricular ejection fraction of at least 55% (as measured by echocardiogram). Patients are also required to have adequate organ function and bone marrow function. Patients with HER2-positive breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, carboplatin, and H plus P for 2 cycles. Patients with HER2-low and HR-positive breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, and cisplatin or carboplatin for 2 cycles. Patients with HER2-low and HR-negative breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, and anthracycline (epirubicin, pirarubicin or liposomal doxorubicin) for 2 cycles. For patients who have responses of stable disease assessed by magnetic resonance imaging will receive T-DXd neoadjuvant therapy. T-DXd will be administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight for 4 cycles. Peripheral blood and biopsy tissue will be collected before neoadjuvant chemotherapy and T-DXd neoadjuvant therapy, and peripheral blood and surgical tissue will be collected after the surgery. Lipid metabolites in peripheral blood and mass spectrometry-based protein quantification in tissue will be detected to find sensitive biomarkers for T-DXd neoadjuvant therapy. The primary endpoint is pCR rate (ypT0/Tis ypN0) and identify sensitive biomarkers for T-DXd neoadjuvant therapy. Secondary endpoints include objective response rate, breast-conserving rate and invasive disease-free survival. Citation Format: Jin Zhang, Zhendong Shi, Jingjing Liu. An exploratory study of Trastuzumab Deruxtecan neoadjuvant therapy in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-04.

Abstract PO5-04-12: Comparison of chemotherapy efficacy in metastatic lobular vs. ductal breast cancer

Abstract Comparison of chemotherapy efficacy in metastatic lobular vs. ductal breast cancer Background: Invasive lobular carcinomas (ILC) are thought to be less chemo-sensitive than invasive ductal carcinomas (IDC), as reflected by lower rates of pathological complete response following neoadjuvant therapy. In the metastatic setting, evidence regarding chemotherapy (Cx) efficacy is limited. Methods: A retrospective review of prospectively collected data for consecutive patients (pts) with metastatic ILC (mILC) treated at a single institution between 2000 and 2023 was included. Pts with mILC were matched on a 1:2 ratio with a cohort of pts with metastatic IDC (mIDC) by age, era of diagnosis and initial metastatic burden. Primary outcome was efficacy of Cx in mILC vs. mIDC pts as measured by time to next treatment - TTNTc (months (m) between start date of first & second Cx). Key secondary endpoints included differences in efficacy of endocrine therapy between the two groups (as measured by TTNT and outcomes in pts with endocrine resistance (EnR) as defined by ESMO consensus guideline) and overall survival (time from diagnosis of metastatic breast cancer (BC) to death or last follow-up [OS]). Results: 376 pts were included, mILC (122) and mIDC (254) with median age 64y and 62y, respectively. A significantly higher proportion of mILC pts had hormone receptor positive/HER2 negative or lower proportion of triple negative disease (p< 0.0001). Compared to mIDC, mILC pts were more likely to have de novo disease (29% vs. 18%; p=0.02), lower grade (p< 0.0001), received endocrine therapy only (p=0.03) and were less likely to have visceral disease at diagnosis or any time after metastatic diagnosis (20% vs. 45% p< 0.0001, 35% vs. 51% < 0.0004, respectively). Median time to commencing chemotherapy from metastatic diagnosis was longer in mILC pts (5.8 v 2.0 m, p=0.03). There was no significant differences in TTNTc for patients with mILC and mIDC except for those with visceral disease at diagnosis (Table 1). There was no significant difference in TTNTc by histological subtype of mILC (p=0.46) or by choice of first line chemotherapy used (p=0.91). In the entire population, no significant OS difference observed in mILC and mIDC (Table 1). BC outcome was assessed in pts receiving endocrine therapy as first-line treatment (mILC 65, mIDC 102). There was no difference in TTNT (mILC 14.6m vs. mIDC 14.8m). There were no differences in incidence of EnR between the groups. OS was shorter in mILC pts with primary EnR. The presence of primary, secondary or no resistance within each histological group was significantly associated with OS (Table 1). Conclusion: Pts with mILC have a longer time to commencing chemotherapy, but efficacy of chemotherapy is similar to pts with mIDC; irrespective of lobular histologic subtype, first line chemotherapy regimen used and sites of disease, except for those mILC with visceral disease. There was no significant difference in OS between mILC and mIDC pts treated in this single centre study. Efficacy of endocrine treatment when given as first line treatment was similar in both groups with no significant difference when pts were evaluated by presence or absence of endocrine resistance, except for primary EnR, but pt numbers were small in this group. Our results demonstrate equivalent chemotherapy efficacy in pts with mILC as compared to mIDC.

Abstract PO1-05-09: ASCENT-07: A phase 3, randomized, open-label study of sacituzumab govitecan versus treatment of physician’s choice in patients with HR+/HER2– inoperable, locally advanced, or metastatic breast cancer post-endocrine therapy

Abstract Background: Approximately 70% of all breast cancer (BC) cases are hormone receptor positive/human epidermal growth factor receptor 2-negative (HR+/HER2–), with ~65% of these being HR+/HER2-low (immunohistochemistry [IHC]1+, IHC2+/in situ hybridization [ISH]–). Despite an increasing number of available endocrine and targeted treatments for metastatic disease, tumors eventually develop resistance to endocrine therapy (ET). Chemotherapy, the standard of care for patients (pts) whose cancers no longer respond to ET, is associated with poor outcomes, representing a high unmet need in the first-line endocrine-resistant setting. Sacituzumab govitecan (SG) is a Trop-2–directed antibody-drug conjugate (ADC) that delivers SN-38 (the active metabolite of the topoisomerase inhibitor irinotecan) to tumor cells via internalization, and to the surrounding tumor microenvironment via the bystander effect. SG demonstrated a significant and clinically meaningful survival benefit in the phase 3, randomized TROPiCS-02 trial, and is approved in the US for inoperable, locally advanced, or metastatic HR+/HER2– BC after ET and ≥ 2 systemic therapies in the metastatic setting. ASCENT-07 will examine the efficacy and safety of SG in the first-line chemotherapy setting, ie, in patients with inoperable, locally advanced, or metastatic ET resistant HR+/HER2– BC. Study design: ASCENT-07 (NCT05840211) is a randomized, open-label, global study evaluating SG versus treatment of physician’s choice (TPC) chemotherapy in pts with HR+/HER2– inoperable, locally advanced, or metastatic BC who have received ET and are eligible for their first chemotherapy for advanced/metastatic disease. Pts aged ≥ 18 years with histologically confirmed HR+/HER2– (HER2 IHC0 or HER2-low [IHC1+, IHC2+/ISH–]) according to ASCO/CAP criteria, measurable disease per RECIST v1.1, and ECOG performance status of 0 or 1 will be included. Pts are eligible if they meet ≥ 1 of the following criteria: progressive disease (PD) in the metastatic setting on ≥ 2 lines of ET (± targeted therapy) (disease recurrence within the first 24 months of starting adjuvant ET is considered a line of therapy), PD within 6 months of first-line ET (± CDK 4/6 inhibitor) in the metastatic setting, or disease recurrence within 24 months of adjuvant ET with CDK 4/6 inhibitor initiation and no longer a candidate for additional ET. PD on the most recent therapy will be documented by CT or MRI per RECIST v1.1. Key exclusion criteria include prior treatment targeting topoisomerase I. Pts will be randomized to SG 10 mg/kg IV on days 1 and 8 of a 21-day cycle or TPC (capecitabine, paclitaxel, nab-paclitaxel). The primary endpoint is progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1 criteria or death from any cause, whichever comes first. Secondary endpoints include PFS (assessed by the investigator), overall survival, objective response rate and duration of response per BICR and investigator, and quality of life (QoL) assessed using the EORTC QLQ-C30 cancer questionnaire (primarily change in the Physical Functioning domain at week 16 and time to deterioration in the Global Health Status/QoL domain). Pharmacokinetics and immunogenicity analyses will be undertaken in pts receiving SG. Incidence of adverse events and serious adverse events, including relationship to study drug(s), will be reported. Laboratory and vital signs will be monitored. ASCENT-07 is currently open for recruitment and requires ~654 eligible pts to provide adequate power for assessment of the primary and key secondary endpoints. Citation Format: Hope Rugo, Javier Cortés, Giuseppe Curigliano, Carlos Barrios, Kevin Punie, Yeon Park, Hiroji Iwata, Alex Young, Xuehan Ren, Pelin Cinar, Komal Jhaveri. ASCENT-07: A phase 3, randomized, open-label study of sacituzumab govitecan versus treatment of physician’s choice in patients with HR+/HER2– inoperable, locally advanced, or metastatic breast cancer post-endocrine therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-09.

Abstract PO1-16-06: LuciA-15 - A real-world prospective study of PARP inhibitors for the treatment of Latin American patients with HER-2 negative metastatic breast cancer with mutation of BRCA1/2 genes or in the Homologous Recombination Repair genes

Abstract Background PARP inhibitors (PARPi) improves progression free survival among patients with HER2 negative (HER2-ve) advanced breast cancer (ABC) and a BRCA1 or BRCA2 mutation compared to physician choice of chemotherapy (CT). The AIM of this prospective study was to evaluate the clinical benefit of PARPi treatment in terms of response, outcomes and survival by breast cancer type and treatment in a Latin-American population. Methods We analyzed data of patients with HER2-ve ABC with germline and/or somatic mutation of BRCA 1 or BRCA 2 or in the Homologous Recombination Repair genes, treated with olaparib or talazoparib in daily clinical practice by oncologist from Argentina and México. From September 2019 and April 2023, we collected baseline characteristics, previous systemic treatments, type and pattern of use, treatment beyond PARPi progression, and patient predisposition. Objective responses, best response rate, real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were analyzed with R software and RStudio version 14.0. Results After a median follow-up of 18.07 months (CI95% 10.53 - 30.07), 51 patients were treated with PARPi. Mean age at start treatment was 47,08 years. 62.7% had ER+ve/HER2-ve and 35.3% had triple negative breast cancer (TNBC). 62.7% and 37.3% of patients received talalaparib and olaparib, respectively. BRCA 1 and 2 germline mutations were the most common alterations found in 96% of patients. 37.5% of patients received platinum-based CT (PbCT) in the (neo)adjuvant/metastatic setting. 57.5% had visceral metastasis and the median number of metastatic sites were 2 (range 1-4). Median number of lines at the time to start PARPi was 2 (range 0-8), 23.5% and 31.4% received PARPi in the 1st line and 2nd line, respectively. The rwORR was 47.0%, and the median rwPFS1 was 7.77 months (CI95% 5.67-14.7). There was a tendence of better rwPFS1 in patients without previous CT versus previous CT in the advance setting, 14.30 months (CI95% 6.47-NR) versus 6.37 months (CI95% 5.03-8.73), respectively (p 0.084). The median rwOS was 26.97 months (CI95% 13.50-NR) and higher in the subgroup of patients naïve for CT versus previous exposure to CT in the advance setting, the median rwOS was 32.1 months (CI95% 27.0-NR) versus 13.0 (IC95%10.1-NR), respectively (p 0.022). 23.5% of patients progressed on PARPi during the first 6 months of treatment, 32.4% with visceral compromise, 27.8% with visceral crisis, and 26.5% with ≥2 metastatic sites. CT was the treatment of choice in most patients (55.3%). The medium rwPFS2 (next treatment after PARPi failure) was 4.00 months (CI95% 3.43 – 7.13). Treatment was discontinued for adverse events in 4.0 % of patients. Conclusion This is the first Latin-American evidence that replicate the data already published in randomized clinical trials and other scanty real-world evidence studies in this field, positive results in rwORR and rwPFS, encouraging data in rwOS. Notably, high proportion of patients with visceral progression even with visceral crisis and need for CT. Interestingly, similar rwOS results among subgroups (TNBC versus ER+ve/HER2-ve, talazoparib versus Olaparib, etc). <graphic> Citation Format: Fernando E. Petracci, Cynthia Villarreal-Garza, Facundo Argañaraz, Gonzalo Gómez Abuin, José Peñaloza, Marcos A. Flores, Luciano Piazzoni, Cecilia Riggi, Lucía Fabiano, Lucía González, Belén Cieplinski, Sergio Rivero, Ernesto Korbenfeld, Pablo Mandó. LuciA-15 - A real-world prospective study of PARP inhibitors for the treatment of Latin American patients with HER-2 negative metastatic breast cancer with mutation of BRCA1/2 genes or in the Homologous Recombination Repair genes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-06.

Abstract PO1-01-04: The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis

Abstract Background In patients with the HR+/HER2+ breast cancer (BC) subtype, it can be more challenging to achieve pathological complete response (pCR) after neoadjuvant therapy compared with the HR-/HER2+ subtype. The importance of neoadjuvant therapy and the association of pCR with long-term clinical benefits have been widely demonstrated in HER2+ BC. This network meta-analysis aimed to identify the optimal anti-HER2 regimen, the role of endocrine therapy, and the better chemotherapy choice for the neoadjuvant treatment of HR+/HER2+ BC patients. Methods Literature for neoadjuvant clinical trials in HR+/HER2+ breast cancer was searched in Medline, EMBASE, Cochrane Library, and Web of Science for publications released before June 2023. Single-arm trials, retrospective studies, and observational studies were excluded, as well as studies containing no neoadjuvant phase and/or no anti-HER2 drugs. A network meta-analysis with the fixed-effect model in a Bayesian framework was performed. Odds ratios (ORs) with 95% confidence intervals (CI) for pathological complete response (pCR) analysis and hazard ratios (HRs) with 95% CI for event-free survival (EFS) were calculated. A ranking of treatment patterns was performed using SUCRA. (Registered in PROSPERO: CRD42023385644 Results 2,844 records were identified by the literature search, 60 trials were included after the screening, and valid data were extracted. 19 trials and 2,883 patients were included in the primary analysis of pCR. Compared with trastuzumab + chemotherapy (CT), three treatment regimens showed significantly higher pCR rates, T-DM1 based treatment (T-DM1, OR: 2.83, 95% CI: 1.90, 4.27; which includes T-DM1 alone, T-DM1 + pertuzumab or T-DM1 + endocrine therapy), trastuzumab + pertuzumab + CT (PH, OR: 2.57, 95% CI: 1.70, 3.94), and trastuzumab + tyrosine kinase inhibitor (TKI)+ CT (H+TKI, OR: 1.60, 95% CI: 1.22, 2.09; TKI includes lapatinib, neratinib and pyrotinib). The SUCRA ranking of pCR showed that T-DM1 was ranked first (SUCRA: 0.94), followed by PH (SUCRA: 0.85) and H+TKI (SUCRA: 0.60). PH came first in the SUCRA ranking of EFS (SUCRA: 0.74) as well as cumulative SUCRA combining pCR and EFS (SUCRA: 0.79). For chemotherapy strategies, platinum-containing regimens showed no significant increase in pCR rate compared to no platinum regimens (OR: 1.27, 95% CI: 0.95, 1.69), regimens with anthracycline also had no statistical difference from those without anthracycline (OR: 0.74, 95% CI: 0.51, 1.07). When assessing the impact of endocrine therapy, no significant difference in pCR rate was observed with or without endocrine therapy (OR: 1.18, 95% CI: 0.80, 1.73). Conclusions The PH regimen remains the best neoadjuvant treatment choice for HR+/HER2+ early BC patients considering pCR and EFS outcomes simultaneously. H+TKI did not show significant benefits, so it is not recommended to be given priority in clinical practice. The platinum-containing regimen’s potential benefit compared to the non-platinum regimen is uncertain and needs more clinical investigation. The necessity of adding endocrine therapy is not proven due to limited data availability. Funding: This study was sponsored by Shanghai Roche Pharmaceuticals Ltd. Disclosure: Hao Tang, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Yajing Feng, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Xin Yu, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Citation Format: Hao Wang, Shiwei Liu, Miao Yu, Kun Mi, Exian Mou, Li Xia, Weimin Xie, Hao Tang, Yajing Feng, Xin Yu. The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-04.

Standardizing eligibility and patient selection for Pressurized Intraperitoneal Aerosol Chemotherapy: A Delphi consensus statement

IntroductionPressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a procedure for minimally invasive drug administration in patients with peritoneal metastasis. Previous studies have emphasized the importance of uniformity in treatment protocols and standardization of this practice. This study aimed to reach a consensus on eligibility, patient selection, and choice of chemotherapy for PIPAC. MethodsA three-round modified Delphi study was conducted. A steering group formulated a list of baseline statements, addressing the objectives. The steering group consisted of seven expert surgical and medical oncologists. Available evidence and published key opinions were critically reviewed. An international expert panel scored those statements on a 4-point Likert scale. The statements were submitted electronically and anonymously. Consensus was reached if the agreement rate was ≥75%. A minimum Cronbach's alpha of >0.8 was set. ResultsForty-five (45/58; 77.6%) experts participated and completed all rounds. Experts were digestive surgeons (n = 28), surgical oncologists (n = 7), gynecologists (n = 5), medical oncologists (n = 4), and one clinical researcher. Their assessment of 81 preliminary statements in the first round resulted in 41 consolidated statements. In round two, consensus was reached on 40 statements (40/41; 97.6%) with a consensus of ≥80% for each individual statement. In the third round, 40 statements were unanimously approved as definitive. The choice of first- and second-line chemotherapy remained controversial and could not reach consensus. ConclusionsThis International Delphi study provides practical guidance on eligibility and patient selection for PIPAC. Ongoing trial data and long-term results that could contribute to the further standardization of PIPAC are eagerly awaited.

Abstract LB082: A high-throughput immune-oncology screen identifies immunostimulatory properties of low dose chemotherapy in triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous subtype broadly characterized by the lack of hormone receptor (HR) and HER2 expression. Compared to HR+ breast cancers, TNBCs typically have a greater immune cell infiltrate and are more likely to respond to immune checkpoint inhibition (ICI). The results from KEYNOTE-355 and KEYNOTE-522 trials led to the approvals of anti-PD-1 in combination with physician’s choice chemotherapy for the treatment of TNBC in adjuvant and neoadjuvant settings. However, few patients achieve a durable response, and there remains a need to optimize combination strategies to enhance the benefits of ICI in TNBC. Therefore, we developed a high-throughput co-culture screening assay to identify compounds enhancing T-cell-mediated cytotoxicity. Co-cultures included three cell types: mKate2-labeled PyMT tumor cells expressing the OVA antigen, BPF-labeled PyMT cells, and CD8+ OT-1 T-cells. The screening library included over 400 FDA-approved compounds or agents under investigation for oncology indications. Each compound was evaluated at five concentrations (3µM-12nM) and across three-time points (24hr, 48hr, and 72hr) to provide insight into the kinetics. Cell viability was assessed via image analysis at each time point, and enhanced cell death in the PyMT-OVA cells compared to the non-OVA PyMT cells was considered evidence of enhanced T-cell mediated cytotoxicity. Five chemotherapy agents were chosen as priority hits for mechanistic follow-up due to their ability to enhance T-cell mediated cytotoxicity at multiple doses and multiple timepoints: paclitaxel, bleomycin sulfate, kinesin-inhibitor, ABT-751, and etoposide. We are exploring the dose dependency of MHC-I and MHC-II induction, as well as the minimum dose required to cause immunogenic cell death. We further found that low doses of these agents do not negativity affect CD8+ T-cell proliferation, whereas high doses may have deleterious effects on CD8+ T-cell functioning. The results of these studies provide mechanistic insight into potential new chemotherapy partners to enhance anti-PD-1 efficacy in TNBC patients and suggest benefit to further investigating the immunostimulatory potential of low dose chemotherapy. Citation Format: Kennady K. Bullock, Thomas Hasaka, Emily Days, Joshua Bauer, Ann Richmond. A high-throughput immune-oncology screen identifies immunostimulatory properties of low dose chemotherapy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB082.

First Line Chemotherapy in Metastatic Colorectal Cancers: A Review

Colorectal cancer (CRC) is a common malignancy detected. Approximately, 22% of CRCs are metastatic at initial diagnosis, and about 70% of patients will eventually develop metastatic relapse. Metastatic colorectal cancer is a disease with poor prognosis whose treatment is always palliative chemotherapy. Today, thanks to the knowledge of molecular biology and the discoveries of new pathways, we have managed to increase survival to around 40 months which can increase thanks to the use of surgery and locoregional treatments. The choice of chemotherapy in these patients therefore depends on the characteristics of the molecular profile and includes, in fit patients, chemotherapy with the addition of targeted therapies. In this article, we examine the most recent data from randomized clinical trials supporting the use of chemotherapy triplets or doublets as well as the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents.

Abstract 1187: Sensitization to chemo-immunotherapy by targeting TGF-β in preclinical triple negative breast cancer models

Abstract Metastatic triple-negative breast cancer (mTNBC) is refractory to anti-PD-(L)1 immunotherapy. In order to sensitize it, preclinical data show the value of adding chemotherapy treatment for its ability to induce immunogenic cancer cell death (Kroemer et al, 2013). This would enable the recruitment of cytotoxic T-CD8+ lymphocytes (CTL) and thus initiate an antitumor immune response to sensitize tumors to immunotherapy. Nevertheless, the results of clinical trials using chemo-immunotherapy combinations are divergent (IMpassion 130 and 131). The IMpassion 130 trial demonstrated the efficacy of nab-paclitaxel and atezolizumab (anti-PD-L1) in PD-L1+ patients, but unfortunately, IMpassion 131 with paclitaxel did not replicate these results. The choice of chemotherapy to combine with immunotherapy appears to be crucial for inducing an antitumor immune response. Optimizing chemo-immunotherapy combinations is a major challenge in the management of TNBC. The initial aim of this project was to evaluate the immune effects of an experimental chemotherapy doublet, based on two drugs used in mTNBC: cisplatin (CDDP) and eribulin. The idea was to find an alternative to the use of taxanes in combination with anti-PD-(L)1.The effect of the two molecules, alone or in combination, was evaluated on immunogenic death stigmata, modulation of effector or immunosuppressive immune populations and stromal populations, and sensitization to anti-PD-L1 immunotherapy in the immunologically "cold" model: 4T1. The in vivo studies has been realized by generation of orthotopic 4T1 tumors, the analysis of the immune infiltration was performed by RT-qPCR, IHC and flow cytometry. In vitro, our results indicate that CDDP, and more intensely in combination with eribulin, significantly induces the various immunogenic death stigmas. In vivo, the therapeutic effect of chemotherapies is limited, with a superior effect of CDDP and the combination. Nevertheless, CTL recruitment and functionality induced by CDDP are significantly enhanced by eribulin. Despite these data pointing to a potential therapeutic synergy with anti PD-L1 immunotherapy, chemo-immunotherapy treatment fails to induce a superior treatment effect. The significant increase in a TGF-β signature induced by the combination in parallel with CTL recruitment explains this resistance. The results show that inhibition of TGF-β, combined with chemo-immunotherapy in the 4T1 model, leads to a reduction in tumor immunosuppression and intratumoral fibrosis, as well as an increase in CTL infiltration and cytotoxicity, enabling tumor sensitization. Overall, this project highlights the benefits of using an experimental doublet of CDDP and eribulin-based chemotherapies. This project demonstrates that management of chemo-induced immunosuppression mechanisms is necessary to overcome tumor resistance to immunotherapy. Citation Format: Laura Kalfeist, Fanny Ledys, Stacy Petit, Samia Kada-Mohammed, Mickael Rialland, François Ghiringhelli, Emeric Limagne, Sylvain Ladoire. Sensitization to chemo-immunotherapy by targeting TGF-β in preclinical triple negative breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1187.

Sacituzumab Govitecan: A Review in Unresectable or Metastatic HR+/HER2- Breast Cancer.

Sacituzumab govitecan (TRODELVY®) is a first-in-class trophoblast cell-surface antigen 2 (Trop-2)-directed antibody and topoisomerase I inhibitor conjugate that is approved globally as monotherapy for the treatment of adults with unresectable locally advanced or metastatic, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-; defined as immunohistochemistry 0, 1+ or 2+ and in situ hybridization-negative) breast cancer who have received endocrine-based therapy and ≥2 additional systemic therapies in the advanced setting. In the phase III TROPiCS-02 trial, intravenous sacituzumab govitecan demonstrated statistically significant and clinically meaningful improvements in progression-free survival and overall survival compared with physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine or vinorelbine) in adults with metastatic HR+/HER2- breast cancer. Sacituzumab govitecan had a generally manageable tolerability profile in these patients; the most common treatment-related grade ≥3 adverse events included neutropenia, diarrhoea, leukopenia, anaemia, fatigue and febrile neutropenia. Sacituzumab govitecan carries regulatory warnings for severe neutropenia and severe diarrhoea. Sacituzumab govitecan demonstrated an overall benefit in terms of health-related quality of life. Current evidence indicates that sacituzumab govitecan is an effective treatment option, with a generally manageable tolerability profile, for patients with pre-treated, unresectable locally advanced or metastatic HR+/HER2- breast cancer.

Single-Agent Trabectedin Versus Physician's Choice Chemotherapy in Patients With Recurrent Ovarian Cancer With BRCA-Mutated and/or BRCAness Phenotype: A Randomized Phase III Trial.

Literature evidence suggests that trabectedin monotherapy is effective in patients with recurrent ovarian cancer (OC) presenting BRCA mutation and/or BRCAness phenotype. A prospective, open-label, randomized phase III MITO-23 trial evaluated the activity and safety of trabectedin 1.3 mg/m2 given once every 3 weeks (arm A) in BRCA 1/2 mutation carriers or patients with BRCAness phenotype (ie, patients who responded to ≥two previous platinum-based treatments) with recurrent OC, primary peritoneal carcinoma, or fallopian tube cancer in comparison with physician's choice chemotherapy in the control arm (arm B; pegylated liposomal doxorubicin, topotecan, gemcitabine, once-weekly paclitaxel, or carboplatin). The primary end point was overall survival (OS) evaluated in the intention-to-treat population. Overall, 244 patients from 21 MITO centers were randomly assigned (arm A = 122/arm B = 122). More than 70% of patients received ≥three previous chemotherapy lines and 35.7% had received a poly (ADP-ribose) polymerase inhibitor (PARPi) before enrollment. Median OS was not significantly different between the arms: arm A: 15.8 versus arm B: 17.9 months (P = .304). Median progression-free survival was 4.9 months in arm A versus 4.4 months in arm B (P = .897). Among 208 patients evaluable for efficacy, the objective response rate was 17.1% in arm A and 21.4% in arm B, with comparable median duration of response (5.62 v 5.66 months, respectively). No superior effect was observed for trabectedin in the prespecified subgroup analyses according to BRCA mutational status, chemotherapy type, and pretreatment with a PARPi and/or platinum-free interval. Trabectedin showed a higher frequency of grade ≥3 adverse events (AEs), serious AEs, and serious adverse drug reactions compared with control chemotherapy. Trabectedin did not improve median OS and showed a worse safety profile in comparison with physician's choice control chemotherapy.

Phase 3 KEYNOTE-992 study of pembrolizumab plus chemoradiotherapy versus placebo plus chemoradiotherapy in patients with muscle-invasive bladder cancer (MIBC).

TPS720 Background: Concurrent chemoradiotherapy (CRT) is a recommended treatment option for patients (pts) with MIBC who seek a bladder-preserving alternative to radical cystectomy and/or not candidates for radical cystectomy. The anti–PD-1 antibody pembrolizumab is approved for metastatic bladder cancer and non–muscle-invasive bladder cancer (NMIBC). The randomized, double-blind, phase 3 KEYNOTE-992 study (NCT04241185) is evaluating efficacy and safety of pembrolizumab plus CRT versus placebo plus CRT in pts with MIBC who chose bladder preservation. Methods: Eligibility criteria include adultswho have a histologically confirmed initial diagnosis of MIBC (T2-T4aN0M0) with ≥50% urothelial histology, ECOG PS score of 0 to 2, have received no prior therapy with anti–PD-1/L1 or agents directed to another stimulatory or coinhibitory T-cell receptor, and have planned treatment with one of the specified radiosensitizing chemotherapies. Prior treatment for NMIBC with intravesical instillation therapy such as BCG or intravesical chemotherapy is permitted. Approximately 636 pts will be randomly assigned 1:1 to receive pembrolizumab 400 mg IV or placebo IV every 6 weeks for up to 9 cycles, both with CRT. Investigator’s choice of chemotherapy will be specified before random assignment. Pts will be stratified by ECOG PS (0 and 1 vs 2), PD-L1 combined positive score (<10 vs ≥10), T stage (T2 vs T3 and T4), and geographic region (United States vs European Union vs rest of the world). Radiosensitizing chemotherapy will be cisplatin monotherapy (35 mg/m2 IV weekly on day 1), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) plus mitomycin C (12 mg/m2 on day 1), or gemcitabine monotherapy (27 mg/m2 IV twice weekly on days 1 and 4). Radiation therapy will be conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). Imaging via CT and CT urography or magnetic resonance urography will be performed 10 weeks after completion of CRT, every 12 weeks until the end of year 2, then every 24 weeks thereafter. Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of treatment (90 days for serious AEs). Primary end point is bladder-intact event-free survival (defined as time from random assignment to first documented occurrence of residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause) as assessed by blinded independent central review and/or central pathology review. Secondary end points are overall survival, metastasis-free survival, time to cystectomy, time to occurrence of NMIBC, safety and tolerability, and patient-reported outcomes. Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT04241185 .

Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial

AbstractGuadecitabine is a novel hypomethylating agent (HMA) resistant to deamination by cytidine deaminase. Patients with relapsed/refractory acute myeloid leukemia (AML) were randomly assigned to guadecitabine or a preselected treatment choice (TC) of high-intensity chemotherapy, low-intensity treatment with HMAs or low-dose cytarabine, or best supportive care (BSC). The primary end point was overall survival (OS). A total of 302 patients were randomly assigned to guadecitabine (n = 148) or TC (n = 154). Preselected TCs were low-intensity treatment (n = 233 [77%; mainly HMAs]), high-intensity chemotherapy (n = 63 [21%]), and BSC (n = 6 [2%]). The median OS were 6.4 and 5.4 months for guadecitabine and TC, respectively (hazard ratio 0.88 [95% confidence interval, 0.67-1.14]; log-rank P = .33). Survival benefit for guadecitabine was suggested in several prospective subgroups, including age <65 years, Eastern Cooperative Oncology Group performance status 0 to 1, refractory AML, and lower peripheral blood blasts ≤30%. Complete response (CR) + CR with partial hematologic recovery rates were 17% for guadecitabine vs 8% for TC (P < .01); CR+CR with incomplete count recovery rates were 27% for guadecitabine vs 14% for TC (P < .01). Safety was comparable for the 2 arms, but guadecitabine had a higher rate of grade ≥3 neutropenia (32% vs 17%; P < .01). This study did not demonstrate an OS benefit for guadecitabine. Clinical response rates were higher for guadecitabine, with comparable safety to TC. There was an OS benefit for guadecitabine in several prespecified subgroups. This study was registered at www.clinicaltrials.gov as #NCT02920008.

A two-arm randomized open-label prospective design superiority phase III clinical trial to compare the efficacy of docetaxel-oxaliplatin-capecitabine/5 fluorouracil (DOC/F) followed by docetaxel versus CAPOX/mFOLFOX-7 in advanced gastric cancers (DOC-GC study).

LBA248 Background: The choice of optimal chemotherapy in advanced (unresectable/metastatic) gastroesophageal junction and gastric (GEJ/G) adenocarcinomas remains undecided with regard to the addition of docetaxel to a FOLFOX/CAPOX backbone in improving outcomes with equipoise with regard to the optimal duration of chemotherapy as well. Methods: The DOC GC study is a multicentric open-label, randomized controlled phase III trial, in adults ≥18 years with advanced GEJ/G adenocarcinoma and adequate end-organ function. Patients were randomized 1:1 to one of two arms: Arm A - modified CAPOX (3 weekly) or modified FOLFOX-7 (2 weekly) for a maximum of 6 months and then observation OR Arm B: modified FLOT (5-FU/leucovorin /Oxaliplatin/Docetaxel) or DOX (docetaxel/oxaliplatin/capecitabine) every 2 weeks for a maximum of four months followed by Docetaxel (60mg/m2) every 3 weeks till disease progression, unacceptable toxicity, or patient's decision to withdraw. The primary endpoint of the study is Overall survival (OS), as calculated by Kaplan-Meier method, while key secondary endpoints include Progression-free survival, and adverse event rates. Results: Of the 324 patients randomized between July 2020 and November 2022, 305 patients were evaluable for analysis (Arm A: 156; Arm B: 149). With a median follow-up time of 19.2 months (95% CI: 16.5 – 21.9) for the entire cohort, the median OS was 10.1 months (95%: 9.2-10.9) in Arm A and 8.9 months (95% CI: 7.3-10.5) in arm B and this difference was not statistically significant [p=0.70]. There were no statistical differences in median PFS between the two arms [Arm A: 7.1 months (95% CI: 6.1-8.1); Arm B: 6.2 months (95% CI: 5.7 – 6.8); p=0.39]. An increased proportion of grade 3/4 neutropenia (21% vs. 5.1%; p&lt;0.001) was seen in patients in Arm B, with other treatment related side effects being comparable between the two arms. A greater proportion of patients in Arm A tended to receive second line therapy compared to Arm B (38% vs. 26%; p=0.07). Conclusions: The addition of docetaxel to a doublet regimen comprising 5-fluorouracil/capecitabine and oxaliplatin did not improve overall survival in patients with advanced GEJ/G cancers. Continuing chemotherapy beyond six months also does not appear to improve survival in this group of cancers. Clinical trial information: CTRI/2020/03/023944 .

Second-line tislelizumab versus chemotherapy in Japanese patients with advanced or metastatic esophageal squamous cell carcinoma: subgroup analysis from RATIONALE-302.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, with limited second-line systemic therapy options, and represents an increasing disease burden in Japan. In the phase 3 RATIONALE-302 study, the anti-programmed cell death protein 1 antibody, tislelizumab, significantly improved overall survival (OS) versus chemotherapy as second-line treatment for advanced/metastatic ESCC. Here, we report the Japanese patient subgroup results. Patients with advanced/metastatic ESCC, with disease progression during/after first-line systemic therapy were randomized 1:1 to open-label tislelizumab 200mg every 3weeks or investigator's choice of chemotherapy (paclitaxel/docetaxel). Efficacy and safety were assessed in all randomized Japanese patients. The Japanese subgroup comprised 50 patients (n = 25 per arm). Tislelizumab improved OS versus chemotherapy (median: 9.8 vs. 7.6months; HR 0.59; 95% CI 0.31, 1.12). Among patients with programmed death-ligand 1 score ≥ 10%, median OS was 12.5months with tislelizumab (n = 10) versus 2.9months with chemotherapy (n = 6) (HR 0.31; 95% CI 0.09, 1.03). Tislelizumab improved progression-free survival versus chemotherapy (median: 3.6 vs. 1.7months, respectively; HR 0.50; 95% CI 0.27, 0.95). Objective response rate was greater with tislelizumab (32.0%) versus chemotherapy (20.0%), and responses were more durable (median duration of response: 8.8 vs. 2.6months, respectively). Fewer patients experienced ≥ grade 3 treatment-related adverse events with tislelizumab (24.0%) versus chemotherapy (47.8%). Tislelizumab demonstrated an improvement in health-related quality of life versus chemotherapy. As second-line therapy for advanced/metastatic ESCC, tislelizumab improved OS versus chemotherapy, with a favorable safety profile, in the Japanese patient subgroup, consistent with the overall population. ClinicalTrials.gov: NCT03430843.

Erythrocyte PIG-A mutant frequencies in cancer patients receiving cisplatin.

Cisplatin is a primary chemotherapy choice for various solid tumors. DNA damage caused by cisplatin results in apoptosis of tumor cells. Cisplatin-induced DNA damage, however, may also result in mutations in normal cells and the initiation of secondary malignancies. In the current study, we have used the erythrocyte PIG-A assay to evaluate mutagenesis in non-tumor hematopoietic tissue of cancer patients receiving cisplatin chemotherapy. Twenty-one head and neck cancer patients undergoing treatment with cisplatin were monitored for the presence of PIG-A mutant total erythrocytes and the young erythrocytes, reticulocytes (RETs), in peripheral blood for up to five and a half months from the initiation of the anti-neoplastic chemotherapy. PIG-A mutant frequency (MF) in RETs increased at least two-fold in 15 patients at some point of the monitoring, while the frequency of total mutant RBCs increased at least two-fold in 6 patients. A general trend for an increase in the frequency of mutant RETs and total mutant RBCs was observed in 19 and 18 patients, respectively. Only in one patient did both RET and total RBC PIG-A MFs did not increase at any time-point over the monitoring period. Cisplatin chemotherapy induces moderate increases in the frequency of PIG-A mutant erythrocytes in head and neck cancer patients. Mutagenicity measured with the flow cytometric PIG-A assay may serve as a tool for predicting adverse outcomes of genotoxic antineoplastic therapy.

Mirvetuximab soravtansine in platinum-resistant recurrent ovarian cancer with high folate receptor-alpha expression: a cost-effectiveness analysis.

Mirvetuximab soravtansine (MIRV), a new antibody-drug conjugate, versus the investigator's choice of chemotherapy (IC) was the first treatment to demonstrate benefits for progression-free and overall survival in platinum-resistant recurrent ovarian cancer (PROC) with high folate receptor-alpha (high-FRα) expression. Efficacy, safety, and economic effectiveness make MIRV the new standard of care for these patients. Based on patients and clinical parameters from MIRASOL (GOG 3045/ENGOT-ov55) phase III randomized controlled trials, the Markov model with a 20-year time horizon was established to evaluate the cost and efficacy of MIRV and IC for PROC with high-FRα expression, considering the bevacizumab-pretreated situation from the American healthcare system. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and incremental net health benefits were the main outcome indicators and compared with willingness-to-pay threshold of $100,000/QALY. Sensitivity and scenario analyses were conducted. Compared with the IC, MIRV was associated with incremental costs of $538,251, $575,674, and $188,248 with the corresponding QALYs (LYs) increased by 0.90 (1.55), 1.09 (1.88), and 0.53 (0.79), leading to ICERs of $596,189/QALY ($347,995/LY), $530,061/QALY ($306,894/LY), and $1,011,310/QALY ($680,025/LY) in the overall, bevacizumab-naïve, and bevacizumab-pretreated patients, respectively. When MIRV is reduced by more than 75%, it may be a cost-effective treatment. At the current price, MIRV for PROC with high-FRα expression is not the cost-effective strategy in the US. However, its treatment has higher health benefits in bevacizumab-naïve patients, which is likely to be an alternative.

Cost-effectiveness of tisotumab vedotin as a second- or third-line therapy for cervical cancer.

To evaluate the cost-effectiveness of tisotumab vedotin to treat recurrent or metastatic cervical cancer in second- or third-line from the U.S. payer perspective. A Markov model with three-state was employed to simulate recurrent or metastatic cervical cancer patients who were administered either tisotumab vedotin or investigator's choice of chemotherapy based on the phase III, open-labeled innovaTV 301 randomized clinical trial. The data on cost and health preferences were collected from the literature. Tisotumab vedotin generated an additional 0.25 quality-adjusted life-years (QALYs) compared to chemotherapy, but at an additional cost of $206,779. This results in incremental cost-effectiveness ratios of $839,107.88 per QALY. The results of the univariate sensitivity analysis indicated that cost of tisotumab vedotin, utility of progressive disease and progression-free survival had the greatest impacts on the outcomes. Probability sensitivity analysis showed that tisotumab vedotin had a 0% chance of being considered cost-effective. Tisotumab vedotin was unlikely cost-effective compared to chemotherapy for recurrent or metastatic cervical cancer patients at a willingness-to-pay threshold of $150,000/QALY from the perspective of a U.S. payer. Lowering the prices of tisotumab vedotin could potentially enhance its cost-effectiveness.